cis-(+/-)-2-(2,3-dihydro-7-methoxybenzofuran-2-spiro-1'-cyclopentane-4-carbonyl)-1,2,3,6-tetrahydrobenzoic acid

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并呋喃
• 英文名称: cis-(+/-)-2-(2,3-dihydro-7-methoxybenzofuran-2-spiro-1'-cyclopentane-4-carbonyl)-1,2,3,6-tetrahydrobenzoic acid
• 英文别名: cis-2-(2,3-dihydro-7-methoxybenzofuran-2-spiro-1'-cyclopentane-4-carbonyl)-1,2,3,6-tetrahydrobenzoic acid；(1S,6R)-6-(7-methoxyspiro[3H-1-benzofuran-2,1'-cyclopentane]-4-carbonyl)cyclohex-3-ene-1-carboxylic acid
• 化学式: C₂₁H₂₄O₅
• 分子量: 356.419
• InChiKey: GCTUPMUEKNZZBC-HIFRSBDPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  72.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  cis-(+/-)-2-(2,3-dihydro-7-methoxybenzofuran-2-spiro-1'-cyclopentane-4-carbonyl)-1,2,3,6-tetrahydrobenzoic acid 在 一水合肼 、 溶剂黄146 作用下， 以 乙醇 为溶剂， 生成 (4aS,8aR)-4-(7-methoxyspiro[3H-1-benzofuran-2,1'-cyclopentane]-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one
  参考文献：
  名称：

  新型选择性磷酸二酯酶（PDE4）抑制剂。4.顺式-四氢和顺式六氢邻苯二氮酮的拆分，绝对构型和PDE4抑制活性。

  摘要：

  最近，我们报道了4-儿茶酚取代的顺-（+/-）-4a，5,6,7,8,8a-六-和顺-（+/-）-4a，5,8,8a-四氢-2H-酞嗪-1-酮显示出对磷酸二酯酶（PDE4）活性的有效抑制作用，而相应的反式外消旋混合物仅表现出弱至中等的活性。为了确定各个顺式对映异构体的绝对构型和PDE4抑制活性，已合成了几种旋光性邻苯二氮酮。用作起始原料的各种γ-酮酸的对映异构体通过形成非对映异构体盐以经典方式拆分，然后以对映选择性的方式将其分别转化为旋光性酞嗪酮。顺式六氢酞嗪酮（+）-12的（+）-对映体的绝对构型通过X射线晶体学测定。发现在4a和8a位置的碳原子分别具有S-和R-构型。在本系列的六氢和四氢邻苯二氮酮中，观察到了对PDE4抑制的立体选择性。邻苯二氮酮的顺-（+）-对映体显示高抑制活性，而它们的（-）-对映体仅显示弱至中等活性。对于顺式（-）-类似物，所有顺式（+）-邻苯二氮酮都可能具有（4

  DOI：

  10.1021/jm0110338
• 作为产物：
  描述：

  5-溴-2-甲氧基苯酚 在 Amberlyst 15 ion-exchange resin 、 potassium tert-butylate 、 potassium carbonate 、 magnesium 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 31.75h， 生成 cis-(+/-)-2-(2,3-dihydro-7-methoxybenzofuran-2-spiro-1'-cyclopentane-4-carbonyl)-1,2,3,6-tetrahydrobenzoic acid
  参考文献：
  名称：

  Novel Selective PDE4 Inhibitors. 2. Synthesis and Structure−Activity Relationships of 4-Aryl-Substituted cis-Tetra- and cis-Hexahydrophthalazinones

  摘要：

  A series of 4-aryl-substituted cis-4a,5,8,8a-tetra- and cis-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-ones with high inhibitory activity toward cAMP-specific phosphodiesterase (PDE4) was synthesized. To study structure-activity relationships various substituents were introduced to the 2-, 3-, and 4-positions of the 4-phenyl ring. Substitution at the 4-position of the phenyl ring was restricted to a methoxy group, probably due to unfavorable steric interactions of larger groups with the binding site. The introduction of many alkoxy substituents including distinct ring systems and functional groups was allowed to the 3-position. It was found that in general the cis-4a,5,8,8a-tetrahydro-2H-phthalazin-1-ones are more potent than their hexahydrophthalic counterparts, the best activity residing in (4-imidazol-1-yl-phenoxy)butoxy analogue 16o (pIC(50) = 9.7).

  DOI：

  10.1021/jm010838c

文献信息

• Novel Selective PDE4 Inhibitors. 2. Synthesis and Structure−Activity Relationships of 4-Aryl-Substituted <i>cis</i>-Tetra- and <i>cis</i>-Hexahydrophthalazinones
  作者：Margaretha Van der Mey、Armin Hatzelmann、Gerard P. M. Van Klink、Ivonne J. Van der Laan、Geert J. Sterk、Ulrich Thibaut、Wolf R. Ulrich、Hendrik Timmerman

  DOI：10.1021/jm010838c

  日期：2001.8.1

  A series of 4-aryl-substituted cis-4a,5,8,8a-tetra- and cis-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-ones with high inhibitory activity toward cAMP-specific phosphodiesterase (PDE4) was synthesized. To study structure-activity relationships various substituents were introduced to the 2-, 3-, and 4-positions of the 4-phenyl ring. Substitution at the 4-position of the phenyl ring was restricted to a methoxy group, probably due to unfavorable steric interactions of larger groups with the binding site. The introduction of many alkoxy substituents including distinct ring systems and functional groups was allowed to the 3-position. It was found that in general the cis-4a,5,8,8a-tetrahydro-2H-phthalazin-1-ones are more potent than their hexahydrophthalic counterparts, the best activity residing in (4-imidazol-1-yl-phenoxy)butoxy analogue 16o (pIC(50) = 9.7).
• Novel Selective Phosphodiesterase (PDE4) Inhibitors. 4. Resolution, Absolute Configuration, and PDE4 Inhibitory Activity of <i>cis</i>-Tetra- and <i>cis</i>-Hexahydrophthalazinones
  作者：Margaretha Van der Mey、Hildegard Boss、Dennis Couwenberg、Armin Hatzelmann、Geert J. Sterk、Kees Goubitz、Henk Schenk、Hendrik Timmerman

  DOI：10.1021/jm0110338

  日期：2002.6.1

  8a-tetrahydro-2H-phthalazin-1-ones show potent inhibition of phosphodiesterase (PDE4) activity, while the corresponding trans racemic mixtures exhibit only weak to moderate activity. To determine the absolute configuration and PDE4 inhibitory activity of the individual cis-enantiomers, several optically active phthalazinones have been synthesized. The enantiomers of the various gamma-keto acids, used as starting

  最近，我们报道了4-儿茶酚取代的顺-（+/-）-4a，5,6,7,8,8a-六-和顺-（+/-）-4a，5,8,8a-四氢-2H-酞嗪-1-酮显示出对磷酸二酯酶（PDE4）活性的有效抑制作用，而相应的反式外消旋混合物仅表现出弱至中等的活性。为了确定各个顺式对映异构体的绝对构型和PDE4抑制活性，已合成了几种旋光性邻苯二氮酮。用作起始原料的各种γ-酮酸的对映异构体通过形成非对映异构体盐以经典方式拆分，然后以对映选择性的方式将其分别转化为旋光性酞嗪酮。顺式六氢酞嗪酮（+）-12的（+）-对映体的绝对构型通过X射线晶体学测定。发现在4a和8a位置的碳原子分别具有S-和R-构型。在本系列的六氢和四氢邻苯二氮酮中，观察到了对PDE4抑制的立体选择性。邻苯二氮酮的顺-（+）-对映体显示高抑制活性，而它们的（-）-对映体仅显示弱至中等活性。对于顺式（-）-类似物，所有顺式（+）-邻苯二氮酮都可能具有（4